This Mentored Clinical Scientist Development Award will provide the candidate with resources necessary to develop a new approach to study the role of opioids in the modulation of nociception. The candidate's current research involves examination of opioid actions on nociceptive primary afferent neurons in an isolated system. This research program will be broadened to include the study of nociceptive transmission within the spinal cord. Noxious stimuli activate nociceptive primary afferent neurons, which form excitatory synaptic connections with secondary nociceptive neurons in several well-defined areas of the spinal dorsal horn. This nociceptive signal is modulated by both excitatory and inhibitory inputs and then relayed from the spinal cord to higher areas. It is unclear how and where in this pathway opioids act to produce analgesia. The goals of the experiments described in this proposal are: 1) to determine whether opioids depress excitatory synaptic responses of nociceptive neurons, augment inhibitory responses, or both; 2) to evaluate the physiologic relevance of presynaptic and postsynaptic inhibitory mechanisms of opioids; and 3) to determine how opioids affect neurons in different parts of the spinal nociceptive pathway. The model system to be used for the proposed experiments is the in vitro rat spinal cord slice preparation. The techniques required for these experiments are demanding and require a significant amount of training to master. In addition, a knowledge of spinal neuronal circuitry and synaptic physiology will be needed to obtain expertise in this new field of study. These goals will be achieved primarily by close mentoring by an investigator experienced in spinal cord slice physiology. Regular meetings with other investigators in the department of Anesthesiology and the Center for Neuroscience who are experienced in synaptic physiology will provide valuable interactions and opportunities for learning. In addition, giving lectures, seminars, and leading graduate students in intensive discussions on topics in spinal nociceptive transmission will enhance career development. Achievement of these goals will allow the candidate to establish an independent scientific research program and a successful academic career combining research, teaching, and clinical care.